► Concentrations of NBFRs, OPFRs and HBCDs are reported in New Zealand indoor dust. ► Concentrations of OPFRs exceed those of PBDEs. ► OPFRs are the major alternative FRs. ► Estimated human exposure ...to alternative FRs is below the reference dose.
Due to worldwide restrictions on polybrominated diphenyl ethers (PBDEs), the demand for alternative flame retardants (AFRs), such as organophosphate flame retardants (OPFRs), novel brominated FRs (NBFRs) and hexabromocyclododecanes (HBCDs), has recently increased. Little is known about human exposure to NBFRs and OPFRs and that their levels in dust have been scarcely evaluated worldwide. To increase the knowledge regarding these chemicals, we measured concentrations of five major NBFRs, ten OPFRs and three HBCD isomers in indoor dust from New Zealand homes. Dust samples were taken from living room floors (n=34) and from mattresses of the same houses (n=16). Concentrations (ngg−1) of NBFRs were: 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) (<2–175), decabromodiphenyl ethane (DBDPE) (<5–1430), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) (<2–2285) and bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate (TBPH) (<2–640). For OPFRs, concentrations (ngg−1) ranged between: tri-ethyl-phosphate (TEP) (<10–235), tri-n-butyl-phosphate (TnBP) (<20–7545), tris-(2-chloroethyl)-phosphate (TCEP) (<20–7605), tris-(1-chloro-2-propyl) phosphate (TCPP) (20–7615), tri-(2-butoxyethyl)-phosphate (TBEP) (50–27325), tris-(2,3-dichloropropyl)-phosphate (TDCPP) (20–16560), tri-phenyl-phosphate (TPhP) (20–35190), and tri-cresyl-phosphate (TCP) (<50–3760). HBCD concentrations fell in the range <2–4100ngg−1. BTBPE, DBDPE, TBPH, TBEP, and TnBP showed significant positive correlation (p<0.05) between their concentrations in mattresses and the corresponding floor dust (n=16). These data were used to derive a range of plausible exposure scenarios. Although the estimated exposure is well below the corresponding reference doses (RfDs), caution is needed given the likely future increase in use of these FRs and the currently unknown contribution to human exposure by other pathways such as inhalation and diet.
•We have developed a new method for the analysis of dialkyl and diaryl phosphates.•OASIS WAX, a weak anion exchange sorbent, had the best performance.•Derivatisation by methylation does not improve ...the analysis of DAPs by LC–MS/MS.•Diphenyl phosphate was the main DAP metabolite in urine.•GC–MS/MS is superior in terms of sensitivity for the chlorinated DAPs.
A new analytical method was developed for the determination of dialkyl and diaryl phosphates (DAPs), which are metabolites of organophosphate triesters (PFRs), in human urine. Target DAPs included dibutyl phosphate (DBP), diphenyl phosphate (DPHP), bis(2-butoxyethyl) phosphate (BBOEP), bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2-propyl) phosphate (BCPP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). Sample preparation was based on solid phase extraction using a weak anion exchange sorbent (Oasis WAX). Although several instrumental techniques have been tested, best results were obtained with reversed phase liquid chromatography–negative electrospray ionisation tandem mass spectrometry (LC–ESI-MS/MS) taking the total analysis time into account. Method accuracy at 3ng/mL in pooled urine ranged between 69 and 119% (recovery), while inter-day imprecision (as relative standard deviation) was <31%. The performance of the LC–MS/MS method was compared to a method based on gas chromatography–electron impact tandem mass spectrometry (GC–MS/MS) and a good correlation (Pearson r=0.82, p<0.01) between the results of these two methods was obtained for DPHP. LC–MS/MS analysis was more suitable for DPHP and BBOEP with respective method limits of quantification (mLOQ) of 0.3 and 0.15ng/mL. In contrast, GC–MS/MS had a better sensitivity for BCEP, BCIPP, and BDCIPP, their respective mLOQs being 0.1, 0.06, 0.02ng/mL, compared to 1.2, 3.7, and 0.5ng/mL by LC–MS/MS. A set of urine samples from volunteers was analysed, in which DPHP was the major DAP metabolite. A significant increase of DPHP levels was observed in the group of smokers (geometric mean of 1.55ng/mL) compared to the non-smokers (geometric mean of 0.88ng/mL). Metabolic transformation of triphenyl phosphate to DPHP by metabolic enzymes induced in smokers could be an explanation for this observation.
Display omitted
•First qualitative metabolism study on EHDPHP using human liver microsomes.•Major phase I metabolites and keto metabolites were hydroxylated.•Glucuronide conjugates of EHDPHP were ...formed in phase II reactions.•Suitable metabolite identification by targeted and untargeted screening.
2-ethylhexyl diphenyl phosphate (EHDPHP) is used as flame retardant and plasticizer additive in a variety of consumer products. Since EHDPHP is toxic to aquatic organisms and has been detected in environmental samples, concerns about human exposure and toxicity are emerging. With the aim of identifying human-specific metabolites, the biotransformation of EHDPHP was investigated using human liver microsomes. Using an in silico program (Meteor) for the prediction of metabolites, untargeted screening tools (agilent Mass Hunter) and a suitable analysis platform based on ultra-high performance liquid chromatography (UPLC) and quadrupole time-of-flight high resolution mass spectrometer (QTOF-MS), for the first time a wide variety of phases-I and II metabolites of EHDPHP were identified. Mono- and di-hydroxylated metabolites, keto metabolites, mixed keto and hydroxylated metabolites and diphenyl phosphate were the major phase-I metabolites of EHDPHP. Glucuronidated metabolites of phase-I metabolites of EHDPHP were also formed by human liver microsomes. Using these results, we propose a general metabolism pathway for EHDPHP in humans and a number of candidate biomarkers for assessing the human exposure to this ubiquitous phosphate flame retardant and plasticizer in future biomonitoring studies. Furthermore, we provide a template analytical approach based on the combination of untargeted and targeted screening and UPLC–QTOF-MS analysis suitable for use in future metabolism studies.
Resorcinol bis(diphenylphosphate) (RDP) is an organophosphorus flame retardant widely used in electric and electronic equipment. It has been detected in house dust of several European countries ...according to recent literature. Similar to other flame retardants, RDP formulations and products treated with RDP, such as plastics, can contain RDP impurities, byproducts and breakdown products. In this study, we use screening methods based on wide scope solvent extraction and high resolution time-of-flight mass spectrometry for the identification of RDP related compounds in products and in dust. We analyzed both plastics from electrical/electronic equipment that contained RDP and indoor dust collected on and around surfaces of this equipment. A variety of compounds, namely TPHP, hydroxylated TPHP and RDP (meta-HO-TPHP and meta-HO-RDP), dihydroxylated TPHP, RDP with the loss of a phenyl group (RDP-Phe) and RDP oligomers were detected in plastics containing high levels of RDP. Regarding dust samples collected on electronics, TPHP meta-HO-TPHP, meta-HO-RDP, RDP-Phe and RDP oligomers were detected. High concentrations of meta-HO-TPHP (20–14 227 ng/g), TPHP (222–50 728 ng/g) and RDP (23–29 118 ng/g) were found in many of the dust samples, so that these compounds seem to easily migrate into the environment. These RDP impurities, byproducts and breakdown products are for the first time reported in indoor dust. Meta-HO-TPHP could be relevant for future biomonitoring studies concerning flame retardants.
•First qualitative metabolism study on PFRs using human liver microsomes.•Rates of substrate depletion were lowest for tris(2-chloroethyl) phosphate.•Tris(dichloropropyl)phosphate metabolism was ...similar to in vivo rat studies.•Triphenyl phosphate was mostly transformed by hydroxylation.•Tris(chloropropyl) phosphate was mostly metabolized by oxidative dehalogenation.
Phosphate flame retardants and plasticizers (PFRs) are additives used in a wide range of polymers. Important representatives, such as tris(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP), tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), have been found in the indoor environment at high levels. Biotransformation of these PFRs needs to be investigated because it can be a major determinant of their bioavailability and toxicity in humans. TBOEP, TPHP, TCEP, TCIPP and TDCIPP were incubated with human liver S9 fraction and microsomes. Supernatants were analyzed using a liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer. Chromatograms were scanned for the presence of Phase-I and Phase-II metabolites and tentatively identified based on mass accuracy of the molecular formula, isotopic pattern, and MS/MS spectra. The two major metabolites of TBOEP were products of O-dealkylation and of hydroxylation, respectively. TPHP was mainly transformed to its diester metabolite by O-dearylation and to a hydroxylated metabolite. TCEP was poorly metabolized into its diester and a product of oxidative dehalogenation. The major metabolite of TCIPP was a product of oxidative dehalogenation. TDCIPP was mainly transformed into its diester and a glutathione S-conjugate. The metabolites identified in the present study are candidate biomarkers for future human biomonitoring studies.
•Nuclear receptor activities of 12 OPFR-metabolites were studied by cell-based assays.•HO-m-TPHP and HO-p-TPHP showed more potent ERα/β agonistic activity than did TPHP.•These HO-TPHPs also acted as ...PXR agonists as well as ERβ, AR and GR antagonists.•Diester OPFR-metabolites and BCIPHIPP did not show any receptor activity.
Organophosphate flame retardants (OPFRs) have been used in a wide variety of applications and detected in several environmental matrices, including indoor air and dust. Continuous human exposure to these chemicals is of growing concern. In this study, the agonistic and/or antagonistic activities of 12 primary OPFR-metabolites against ten human nuclear receptors were examined using cell-based transcriptional assays, and compared to those of their parent compounds. As a result, 3-hydroxylphenyl diphenyl phosphate and 4-hydroxylphenyl diphenyl phosphate showed more potent estrogen receptor α (ERα) and ERβ agonistic activity than did their parent, triphenyl phosphate (TPHP). In addition, these hydroxylated TPHP-metabolites also showed ERβ antagonistic activity at higher concentrations and exhibited pregnane X receptor (PXR) agonistic activity as well as androgen receptor (AR) and glucocorticoid receptor (GR) antagonistic activities at similar levels to those of TPHP. Bis(2-butoxyethyl) 3′-hydroxy-2-butoxyethyl phosphate and 2-hydroxyethyl bis(2-butoxyethyl) phosphate act as PXR agonists at similar levels to their parent, tris(2-butoxyethyl) phosphate. On the other hand, seven diester OPFR-metabolites and 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate did not show any receptor activity. Taken together, these results suggest that hydroxylated TPHP-metabolites show increased estrogenicity compared to the parent compound, whereas the diester OPFR-metabolites may have limited nuclear receptor activity compared to their parent triester OPFRs.
Higher house dust levels of PBDE flame retardants (FRs) have been reported in California than other parts of the world, due to the state’s furniture flammability standard. However, changing levels of ...these and other FRs have not been evaluated following the 2004 U.S. phase-out of PentaBDE and OctaBDE. We analyzed dust collected in 16 California homes in 2006 and again in 2011 for 62 FRs and organohalogens, which represents the broadest investigation of FRs in homes. Fifty-five compounds were detected in at least one sample; 41 in at least 50% of samples. Concentrations of chlorinated OPFRs, including two (TCEP and TDCIPP) listed as carcinogens under California’s Proposition 65, were found up to 0.01% in dust, higher than previously reported in the U.S. In 75% of the homes, we detected TDBPP, or brominated “Tris,” which was banned in children’s sleepwear because of carcinogenicity. To our knowledge, this is the first report on TDBPP in house dust. Concentrations of Firemaster 550 components (EH-TBB, BEH-TEBP, and TPHP) were higher in 2011 than 2006, consistent with its use as a PentaBDE replacement. Results highlight the evolving nature of FR exposures and suggest that manufacturers continue to use hazardous chemicals and replace chemicals of concern with chemicals with uncharacterized toxicity.
Organophosphate flame retardants and plasticizers (PFRs) are a group of chemicals widely added to consumer products. PFRs are quickly metabolized in the human body into two types of metabolites, (1) ...dialkyl and diaryl phosphate esters (DAPs), such as diphenyl phosphate (DPHP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP); and (2) hydroxylated PFRs (HO-PFRs), such as 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) and 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP). Existing analytical methods usually focus on DAPs; therefore, human biomonitoring data on HO-PFRs remain scarce. In this study, an analytical procedure was developed for the simultaneous quantification of multiple PFR metabolites in human urine, covering eight DAPs and six HO-PFRs. Sample preparation was optimized to include all target compounds using Bond-Elut C18 solid-phase extraction cartridges, followed by instrumental analysis based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS). Method performance was validated according to established guidelines and satisfactory results were obtained for all metabolites in terms of recovery, linearity, limits of quantification, precision, and accuracy. Recoveries ranged from 87 to 112%. Method detection limits from 0.002 ng/mL for 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) to 0.66 ng/mL for 4-hydroxyphenyl phenyl phosphate (4-HO-DPHP). Seven PFR metabolites were frequently detected in a small biomonitoring study (
n
= 14), among them bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DNBP), 5-HO-EHDPHP, and BBOEHEP. Highest mean concentrations were found for DPHP, 2-ethylhexyl phenyl phosphate (EHPHP), and BCIPHIPP, while 4-HO-DPHP, 5-HO-EHDPHP, and EHPHP were detected in urine for the first time. Overall, the obtained results demonstrate that the developed method can be used for the simultaneous determination of 14 urinary biomarkers of exposure to PFRs.
Graphical abstract
ᅟ
Ever since the interest in organic environmental contaminants first emerged 50years ago, there has been a need to present discussion of such chemicals and their transformation products using simple ...abbreviations so as to avoid the repetitive use of long chemical names. As the number of chemicals of concern has increased, the number of abbreviations has also increased dramatically, sometimes resulting in the use of different abbreviations for the same chemical. In this article, we propose abbreviations for flame retardants (FRs) substituted with bromine or chlorine atoms or including a functional group containing phosphorus, i.e. BFRs, CFRs and PFRs, respectively. Due to the large number of halogenated and organophosphorus FRs, it has become increasingly important to develop a strategy for abbreviating the chemical names of FRs. In this paper, a two step procedure is proposed for deriving practical abbreviations (PRABs) for the chemicals discussed. In the first step, structural abbreviations (STABs) are developed using specific STAB criteria based on the FR structure. However, since several of the derived STABs are complicated and long, we propose instead the use of PRABs. These are, commonly, an extract of the most essential part of the STAB, while also considering abbreviations previously used in the literature. We indicate how these can be used to develop an abbreviation that can be generally accepted by scientists and other professionals involved in FR related work. Tables with PRABs and STABs for BFRs, CFRs and PFRs are presented, including CAS (Chemical Abstract Service) numbers, notes of abbreviations that have been used previously, CA (Chemical Abstract) name, common names and trade names, as well as some fundamental physico-chemical constants.
► A standard is proposed for abbreviations of brominated, chlorinated and phosphorus containing flame retardants (BFRs, CFRs and PFRs). ► The standard is aimed to simplify and promote scientific communication related to BFRs, CFRs and PFRs. ► Structured abbreviations (STABs) are prepared in close relation to the chemical structure of the BFRs, CFRs and PFRs. ► Practical abbreviations (PRABs) are in general derived from the STABs or from commonly used abbreviations from the past. ► Established, emerging, novel and potential BFRs, CFRs and PFRs are defined.
The demand for alternative flame retardant materials such as phosphate flame retardants and plasticizers (PFRs) is increasing, although little is known of their possible effects on human health and ...development. To date, no information on the exposure of children or general Australian population to PFRs is available. The objectives of this study were to characterize the average levels and age-related patterns of PFR metabolites in urine in the general Australian population and to identify novel hydroxylated PFR metabolites in urine. Surplus pathology urine samples from Queensland, Australia were stratified and pooled by age and sex (3224 individuals aged 0 to 75years into 95 pools) according to two different pooling strategies at two different time periods. Samples were analyzed by solid phase extraction and liquid chromatography–tandem mass spectrometry following enzymatic treatment. Nine PFR metabolites were measured in the Australian population, including the first report of a hydroxylated metabolite of TCIPP (BCIPHIPP). Diphenyl phosphate (DPHP), BCIPHIPP and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were detected in >95% of samples. DPHP, a metabolite of aryl-PFRs, was found in several samples at levels which were one order of magnitude higher than previously reported (up to 730ng/mL). Weighted linear regression revealed a significant negative association between log-normalized BDCIPP and DPHP levels and age (p<0.001). Significantly greater levels of BDCIPP and DPHP were found in children's urine compared with adults, suggesting higher exposure to PFRs in young children. BCIPHIPP was identified for inclusion in future PFR biomonitoring studies.
•Levels and age-related patterns of PFR metabolites in pooled urine•BCIPHIPP (metabolite of TCIPP) was measured for the first time in human urine.•DPHP, BCIPHIPP and BDCIPP were detected in >95% of samples.•DPHP was found in pooled urine up to 730ng/mL.•Significantly greater levels of BDCIPP and DPHP were found in children's urine.
PDF
